U.S. patent application number 10/584946 was filed with the patent office on 2011-06-09 for pyrrolopyrimidine and pyrrolotriazine derivatives.
This patent application is currently assigned to TAISHO PHARMACEUTICAL CO., LTD.. Invention is credited to Ludo E.J. Kennis, Atsuro Nakazato, Dai Nozawa, Taketoshi Okubo, Tomoko Tamita.
Application Number | 20110137031 10/584946 |
Document ID | / |
Family ID | 34746977 |
Filed Date | 2011-06-09 |
United States Patent
Application |
20110137031 |
Kind Code |
A1 |
Nakazato; Atsuro ; et
al. |
June 9, 2011 |
PYRROLOPYRIMIDINE AND PYRROLOTRIAZINE DERIVATIVES
Abstract
An object of the present invention is to provide an antagonist
against CRF receptors which is effective as a therapeutic or
prophylactic agent for diseases in which CRF is considered to be
involved, such as depression, anxiety, Alzheimer's disease,
Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc. A pyrrolopyrimidine or pyrrolotriazine derivative substituted
with a carbamoyl group represented by the following formula [I]:
has a high affinity for CRF receptors and is effective against
diseases in which CRF is considered to be involved.
##STR00001##
Inventors: |
Nakazato; Atsuro; (Tokyo,
JP) ; Okubo; Taketoshi; (Tokyo, JP) ; Nozawa;
Dai; (Tokyo, JP) ; Tamita; Tomoko; (Tokyo,
JP) ; Kennis; Ludo E.J.; (Beerse, BE) |
Assignee: |
TAISHO PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
34746977 |
Appl. No.: |
10/584946 |
Filed: |
January 6, 2005 |
PCT Filed: |
January 6, 2005 |
PCT NO: |
PCT/JP2005/000319 |
371 Date: |
July 5, 2006 |
Current U.S.
Class: |
544/211 ;
544/282 |
Current CPC
Class: |
A61P 37/02 20180101;
A61P 17/00 20180101; C07D 487/04 20130101; A61P 25/24 20180101;
A61P 25/00 20180101; A61P 43/00 20180101; A61P 9/10 20180101; A61P
25/20 20180101; A61P 17/14 20180101; A61P 25/22 20180101; A61P
25/28 20180101; A61P 25/30 20180101; A61P 29/00 20180101; A61P
25/08 20180101; A61P 25/16 20180101; A61P 25/18 20180101; A61P 1/00
20180101; A61P 25/14 20180101; A61P 9/12 20180101 |
Class at
Publication: |
544/211 ;
544/282 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 6, 2004 |
JP |
2004-001311 |
Claims
1. A pyrrolopyrimidine or pyrrolotriazine derivative substituted
with a carbamoyl group represented by the following formula [I]:
##STR00088## (wherein E is N or CR.sup.10; R.sup.1 is --OR.sup.4,
--S(O).sub.1R.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl, halogen, C.sub.1-6alkoxy,
C.sub.3-7cycloalkyloxy, C.sub.1-6alkylthio or --N(R.sup.6)R.sup.7;
R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl or aryl; R.sup.4 and R.sup.5 are
the same or different, and independently hydrogen, C.sub.1-9alkyl,
C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl, cyano-C.sub.1-6alkyl,
carbamoyl-C.sub.1-6alkyl or di(C.sub.1-6alkyl)amino-C.sub.2-6alkyl;
or R.sup.4 and R.sup.5 are taken together to form
--(CH.sub.2).sub.m-A-(CH.sub.2).sub.n-- wherein A is methylene,
oxygen, sulfur, NR.sup.8 or CHR.sup.9; R.sup.6 and R.sup.7 are the
same or different, and independently hydrogen or C.sub.1-6alkyl;
R.sup.8 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl or
aryl-C.sub.1-6alkyl; R.sup.9 is hydrogen, hydroxy,
hydroxy-C.sub.1-6alkyl, cyano or cyano-C.sub.1-6alkyl; R.sup.10 is
hydrogen, halogen or C.sub.1-6alkyl; l is an interger selected from
0, 1 and 2; m is an integer selected from 1, 2, 3 and 4; n is an
integer selected from 0, 1, 2 and 3; with the proviso, when A is
oxygen, sulfur or NR.sup.8, then n is 1, 2 or 3; Ar is aryl or
heteroaryl which aryl or heteroaryl is unsubstituted or substituted
with 1 or more substituents, which are the same or different,
selected from the group consisting of halogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.1-6alkylsulfinyl,
C.sub.1-6alkylsulfonyl, cyano, nitro, hydroxy, --CO.sub.2R.sup.11,
--C(.dbd.O)R.sup.12, --CONR.sup.13R.sup.14, --OC(.dbd.O)R.sup.15,
--NR.sup.16CO.sub.2R.sup.17, --S(.dbd.O).sub.rNR.sup.18R.sup.19,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy
and --N(R.sup.20)R.sup.21; R.sup.11 and R.sup.17 are the same or
different, and independently are hydrogen, C.sub.1-5alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-5alkyl, aryl or
aryl-C.sub.1-5alkyl; R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 are the same or
different, and independently are hydrogen, C.sub.1-5alkyl or
C.sub.3-8cycloalkyl; r is 1 or 2), individual isomers thereof or
racemic or non-racemic mixtures of isomers thereof, or
pharmaceutically acceptable salts and hydrates thereof.
2. The pyrrolopyrimidine derivative substituted with a carbamoyl
group according to claim 1 represented by the following formula
[II]: ##STR00089## (wherein R.sup.1, R.sup.2, R.sup.3 and Ar are as
defined in claim 1), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
3. The pyrrolopyrimidine derivative substituted with a carbamoyl
group according to claim 2 represented by the formula [II], wherein
R.sup.1 is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is
C.sub.1-6alkyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 and
R.sup.5 are the same or different, and independently hydrogen,
C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; Ar is phenyl which
phenyl is substituted with two or three substituents, which are the
same or different, selected from the group consisting of halogen,
C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.20)R.sup.21
(wherein R.sup.20 and R.sup.21 are the same or different, and
independently are hydrogen or C.sub.1-3alkyl), individual isomers
thereof or racemic or non-racemic mixtures of isomers thereof, or
pharmaceutically acceptable salts and hydrates thereof.
4. The pyrrolopyrimidine derivative substituted with a carbamoyl
group according to claim 2 represented by the formula [II], wherein
R.sup.1 is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is
C.sub.1-6alkyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 is
C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; R.sup.5 is
hydrogen; Ar is phenyl which phenyl is substituted with two or
three substituents, which are the same or different, selected from
the group consisting of halogen and C.sub.1-3alkyl, individual
isomers thereof or racemic or non-racemic mixtures of isomers
thereof, or pharmaceutically acceptable salts and hydrates
thereof.
5. The pyrrolotriazine derivative substituted with a carbamoyl
group according to claim 1 represented by the following formula
[III]: ##STR00090## (wherein R.sup.1, R.sup.2, R.sup.3 and Ar are
as defined in claim 1), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
6. The pyrrolotriazine derivative substituted with a carbamoyl
group according to claim 5 represented by the formula [III],
wherein R.sup.1 is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is
C.sub.1-6alkyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 and
R.sup.5 are the same or different, and independently hydrogen,
C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; Ar is phenyl which
phenyl is substituted with two or three substituents, which are the
same or different, selected from the group consisting of halogen,
C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.20)R.sup.21
(wherein R.sup.20 and R.sup.21 are the same or different, and
independently are hydrogen or C.sub.1-3alkyl), individual isomers
thereof or racemic or non-racemic mixtures of isomers thereof, or
pharmaceutically acceptable salts and hydrates thereof.
7. The pyrrolotriazine derivative substituted with a carbamoyl
group according to claim 5 represented by the formula [III],
wherein R.sup.1 is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is
C.sub.1-6alkyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 is
C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; R.sup.5 is
hydrogen; Ar is phenyl which phenyl is substituted with two or
three substituents, which are the same or different, selected from
the group consisting of halogen and C.sub.1-3alkyl, individual
isomers thereof or racemic or non-racemic mixtures of isomers
thereof, or pharmaceutically acceptable salts and hydrates
thereof.
8. An antagonist for CRF receptors, comprising a pyrrolopyrimidine
or pyrrolotriazine derivative substituted with a carbamoyl group, a
pharmaceutically acceptable salt thereof or its hydrate according
to any one of claims 1 to 7, as an active ingredient.
9. Use of a pyrrolopyrimidine or pyrrolotriazine derivative
substituted with a carbamoyl group, a pharmaceutically acceptable
salt thereof or its hydrate according to any one of claim 1 to 7,
for the manufacture of a therapeutic agent as an antagonist for CRF
receptors.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0001] 1. Technical Field
[0002] The present invention relates to a therapeutic agent for
diseases in which corticotropin releasing factor (CRF) is
considered to be involved, such as depression, anxiety, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, epilepsy, dermatitides,
schizophrenia, pain, etc.
[0003] 2. Description of the Prior Art
[0004] CRF is a hormone comprising 41 amino acids (Science, 213,
1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987), and it is
suggested that CRF plays a core role in biological reactions
against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994;
Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452,
1995). For CRF, there are the following two paths: a path by which
CRF acts on peripheral immune system or sympathetic nervous system
through hypothalamus-pituitary-adrenal system, and a path by which
CRF functions as a neurotransmitter in central nervous system (in
Corticotropin Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, pp. 29-52, 1990). Intraventricular administration of
CRF to hypophy-sectomized rats and normal rats causes an
anxiety-like symptom in both types of rats (Pharmacol. Rev., 43,
425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is,
there are suggested the participation of CRF in
hypothalamus-pituitary-adrenal system and the pathway by which CRF
functions as a neurotransmitter in central nervous system.
[0005] The review by Owens and Nemeroff in 1991 summarizes diseases
in which CRF is involved (Pharmacol. Rev., 43, 425-474, 1991). That
is, CRF is involved in depression, anxiety, Alzheimer's disease,
Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastrointestinal diseases, drug dependence,
inflammation, immunity-related diseases, etc. It has recently been
reported that CRF is involved also in epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, and cephalic
external wound (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31,
48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res.
744, 166-170, 1997). Accordingly, antagonists against CRF receptors
are useful as therapeutic agents for the diseases described
above.
[0006] WO98/35967 discloses pyrrolopyrimidines or pyrrolotriazine
derivatives respectively as CRF receptor antagonists. However, none
disclose the compounds provided in the present invention.
Problems(s) to be Solved by Invention
[0007] An object of the present invention is to'provide an
antagonist against CRF receptors which is effective as a
therapeutic or prophylactic agent for diseases in which CRF is
considered to be involved, such as depression, anxiety, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc.
Means for Solving Problem
[0008] The present inventors earnestly investigated
pyrrolopyrimidines or pyrrolotriazines substituted with a carbamoyl
group that have a high affinity for CRF receptors, whereby the
present invention has been accomplished.
[0009] The present invention is pyrrolopyrimidine or
pyrrolotriazine derivatives substituted with a carbamoyl group
explained below.
[0010] A pyrrolopyrimidine or pyrrolotriazine derivative
substituted with a carbamoyl group represented by the following
formula [I]:
##STR00002##
(wherein E is N or CR.sup.10;
[0011] R.sup.1 is --OR.sup.4, --S(O).sub.1R.sup.4 or
--NR.sup.4R.sup.5;
[0012] R.sup.2 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl, halogen, C.sub.1-6alkoxy,
C.sub.3-7cycloalkyloxy, C.sub.1-6alkylthio or
--N(R.sup.6)R.sup.7;
[0013] R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl or aryl;
[0014] R.sup.4 and R.sup.5 are the same or different, and
independently hydrogen, C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl, cyano-C.sub.1-6alkyl,
carbamoyl-C.sub.1-6alkyl or di(C.sub.1-6alkyl)amino-C.sub.2-6alkyl;
or R.sup.4 and R.sup.5 are taken together to form
--(CH.sub.2).sub.m-A-(CH.sub.2).sub.n-- wherein A is methylene,
oxygen, sulfur, NR.sup.8 or CHR.sup.9;
[0015] R.sup.6 and R.sup.7 are the same or different, and
independently hydrogen or C.sub.1-6alkyl;
[0016] R.sup.8 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
aryl or aryl-C.sub.1-6alkyl;
[0017] R.sup.9 is hydrogen, hydroxy, hydroxy-C.sub.1-6alkyl, cyano
or cyano-C.sub.1-6alkyl;
[0018] R.sup.10 is hydrogen, halogen or C.sub.1-6alkyl;
[0019] l is an interger selected from 0, 1 and 2;
[0020] m is an integer selected from 1, 2, 3 and 4;
[0021] n is an integer selected from 0, 1, 2 and 3;
[0022] with the proviso, when A is oxygen, sulfur or NR.sup.8, then
n is 1, 2 or 3;
[0023] Ar is aryl or heteroaryl which aryl or heteroaryl is
unsubstituted or substituted with 1 or more substituents, which are
the same or different, selected from the group consisting of
halogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, cyano, nitro,
hydroxy, --CO.sub.2R.sup.11, --C(.dbd.O)R.sup.12,
--CONR.sup.13R.sup.14, --OC(.dbd.O)R.sup.15,
--NR.sup.16CO.sub.2R.sup.17, --S(.dbd.O).sub.rNR.sup.18R.sup.19,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy
and --N(R.sup.20)R.sup.21;
[0024] R.sup.11 and R.sup.17 are the same or different, and
independently are hydrogen, C.sub.1-5alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-5alkyl, aryl or
aryl-C.sub.1-5alkyl;
[0025] R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.18,
R.sup.19, R.sup.20 and R.sup.21 are the same or different, and
independently are hydrogen; C.sub.1-5alkyl or
C.sub.3-8cycloalkyl;
[0026] r is 1 or 2), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
[0027] The terms used in the present specification have the
following meanings.
[0028] The term "C.sub.1-9alkyl" means a straight chain or branched
chain alkyl group of 1 to 9 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl,
isopentyl, 1-methylbutyl, hexyl, isohexyl, 1-ethylpropyl,
1-ethylbutyl, 1,3-dimethylbutyl, 1-propylbutyl, 1-propylpentyl,
1-butylpentyl or the like.
[0029] The term "C.sub.3-7cycloalkyl" means a cyclic alkyl, group
of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or the like.
[0030] The term "C.sub.3-7cycloalkyl-C.sub.1-6alkyl" means a
substituted C.sub.1-6alkyl group having the above-mentioned
C.sub.3-7cycloalkyl as the substituent, such as cyclopropylmethyl,
1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl,
2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,
1-cyclopropylpropyl, 1-cyclobutylpropyl, 1-cyclopentylpropyl,
1-cyclopropylmethylpropyl, 1-cyclopropylmethylbutyl or the
like.
[0031] The term "C.sub.3-8cycloalkyloxy" means a cyclic alkoxy
group of 3 to 8 carbon atoms, such as cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy or the like.
[0032] The term "di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl" means a
substituted C.sub.1-6alkyl group having two above-mentioned
C.sub.3-7cycloalkyl groups as the substituents, such as
di(cyclopropyl)methyl, di(cyclobutyl)methyl, di(cyclopentyl)methyl
or the like.
[0033] The term "C.sub.1-6alkoxy" means a straight chain or
branched chain alkoxy group of 1 to 6 carbon atoms, such as
methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy,
pentyloxy, isopentyloxy or the like.
[0034] The term "C.sub.1-6alkoxy-C.sub.1-6alkyl" means a
substituted C.sub.1-6alkyl group having the above-mentioned
C.sub.1-6alkoxy group as the substituent, such as methoxymethyl,
2-methoxyethyl, 2-ethoxyethyl, 1-methoxymethylpropyl,
1-methoxymethylbutyl or the like.
[0035] The term "di(C.sub.1-6alkoxy)-C.sub.1-6alkyl" means a
substituted C.sub.1-6alkyl group having two above-mentioned
C.sub.1-6alkoxy groups as the substituents, such as
2,3-di(methoxy)propyl, 2-methoxy-1-methoxymethyl-ethyl,
2,4-di(ethoxy)pentyl or the like.
[0036] The term "hydroxy-C.sub.1-6alkyl" means a substituted
C.sub.1-6alkyl group having a hydroxy group, such as hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl,
1-hydroxymethylpropyl, 1-hydroxymethylbutyl,
1-hydroxymethyl-3-methylbutyl or the like.
[0037] The term "cyano-C.sub.1-6alkyl" means a substituted
C.sub.1-6alkyl group having a cyano group, such as cyanomethyl,
1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 1-cyanobutyl,
5-cyanopentyl, 2-cyano-1-ethylethyl, 1-cyanomethylbutyl,
1-cyano-3-methylbutyl, 1-cyanomethyl-3-methyl-butyl or the
like.
[0038] The term "carbamoyl-C.sub.1-6alkyl" means a substituted
C.sub.1-6alkyl group having a carbamoyl group, such as
carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl,
1-carbamoylpropyl, 1-carbamoylbutyl, 5-carbamoylpentyl,
1-carbamoyl-3-methylbutyl, 1-carbamoylmethylbuty,
1-carbamoylmethylpropyl, 1-carbamoylmethyl-3-methylbutyl or the
like.
[0039] The term "di(C.sub.1-6alkyl)amino" means a amino group
having two above-mentioned C.sub.1-6alkyl groups, such as
dimethylamino, diethylamino, dipropylamino or the like.
[0040] The term "di(C.sub.1-6alkyl)amino-C.sub.2-6alkyl" means a
substituted C.sub.2-6alkyl group having a above-mentioned
di(C.sub.1-6alkyl)amino group, such as 2-dimethylaminoethyl,
3-dimethylaminopropyl or the like.
[0041] The term "aryl" means a monocyclic or bicyclic group of 6 to
12 ring carbon atoms having at least one aromatic ring, such as
phenyl, naphthyl, or the like.
[0042] The term "heteroaryl" means a monocyclic or bicyclic group
of 5 to 12 ring atoms having at least one aromatic ring having in
its ring 1 to 4 atoms which may be the same or different and are
selected from nitrogen, oxygen and sulfur, such as pyridyl,
pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl,
quinoxalinyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl or
the like.
[0043] The term "ary-C.sub.1-5alkyl" means a substituted
C.sub.1-5alkyl group having the above-mentioned aryl as the
substituent, such as benzyl, phenethyl or the like.
[0044] The term "halogen" means fluorine, chlorine, bromine or
iodine atom.
[0045] The term "C.sub.2-6alkenyl" means a straight chain or
branched chain alkenyl group of 2 to 6 carbon atoms, such as vinyl,
isopropenyl, allyl or the like.
[0046] The term "C.sub.2-6alkynyl" means a straight chain or
branched chain alkynyl group of 2 to 6 carbon atoms, such as
ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
[0047] The term "C.sub.1-6alkylthio" means a straight chain or
branched chain alkylthio group of 1 to 6 carbon atoms, such as
methylthio, ethylthio, propylthio or the like.
[0048] The phrase "aryl or heteroaryl which aryl or heteroaryl is
unsubstituted or substituted with 1 or more substituents, which are
the same or different, selected from the group consisting of
halogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, cyano, nitro,
hydroxy, --CO.sub.2R.sup.9, --C(.dbd.O)R.sup.10,
--CONR.sup.11R.sup.12, --OC(.dbd.O)R.sup.13,
--NR.sup.14CO.sub.2R.sup.15, --S(.dbd.O).sub.rNR.sup.16R.sup.17,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy
and --N(R.sup.18)R.sup.19'' includes, for example,
2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dibromophenyl,
2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl,
2-chloro-4-trifluoromethylphenyl, 4-methoxy-2-methylphenyl,
2-chloro-4-trifluoromethoxyphenyl, 4-isopropyl-2-methylthiophenyl,
2,4,6-trimethylphenyl, 4-bromo-2,6-dimethylphenyl,
4-bromo-2,6-diethylphenyl, 4-chloro-2,6-dimethylphenyl,
2,4,6-tribromophenyl, 2,4,5-tribromophenyl, 2,4,6-trichlorophenyl,
2,4,5-trichlorophenyl, 4-bromo-2,6-dichlorophenyl,
6-chloro-2,4-dibromophenyl; 2,4-dibromo-6-fluorophenyl,
2,4-dibromo-6-methylphenyl, 2,4-dibromo-6-methoxyphenyl,
2,4-dibromo-6-methylthiophenyl, 2,6-dibromo-4-isopropylphenyl,
2,6-dibromo-4-trifluoromethylphenyl,
2-bromo-4-trifluoromethylphenyl, 4-bromo-2-chlorophenyl,
2-bromo-4-chlorophenyl, 4-bromo-2-methylphenyl,
4-chloro-2-methylphenyl, 2,4-dimethoxyphenyl,
2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6-dibromophenyl,
4-bromo-2,6-difluorophenyl, 2,6-dichloro-4-trifluoromethylphenyl,
2,6-dichloro-4-trifluoromethoxyphenyl,
2,6-dibromo-4-trifluoromethoxyphenyl, 2-chloro-4,6-dimethylphenyl,
2-bromo-4,6-dimethoxyphenyl, 2-bromo-4-isopropyl-6-methoxyphenyl,
2,4-dimethoxy-6-methylphenyl, 6-dimethylamino-4-methylpyridin-3-yl,
2-chloro-6-trifluoromethyl-pyridin-3-yl,
2-chloro-6-trifluoromethoxypyridin-3-yl,
2-chloro-6-methoxypyridin-3-yl,
6-methoxy-2-trifluoromethylpyridin-3-yl,
2-chloro-6-difluoromethylpyridin-3-yl,
6-methoxy-2-methylpyridin-3-yl, 2,6-dimethoxypyridin-3-yl,
4,6-dimethyl-2-trifluoromethylpyrimidin-5-yl and
2-dimethylamino-6-methylpyridin-3-yl.
[0049] The "pharmaceutically acceptable salts" in the present
invention include, for example, salts with an inorganic acid such
as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric
acid, nitric acid or the like; salts with an organic acid such as
acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid,
maleic acid, citric acid, benzenesulfonic acid, methanesulfonic
acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid,
ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic
acid, glycolic acid, malic acid, malonic acid, mandelic acid,
galactaric acid, naphthalene-2-sulfonic acid or the like; salts
with one or more metal ions such as lithium ion, sodium ion,
potassium ion, calcium ion, magnesium ion, zinc ion, aluminium ion
or the like; salts with an amine such as ammonia, arginine, lysine,
piperazine, choline, diethylamine, 4-phenylcyclohexylamine,
2-aminoethanol, benzathine or the like.
[0050] In a compound of the present invention, isomers such as
diastereomers, enantiomers, geometricisomers and tautomeric forms
may exist. The compound of the present invention includes the
individual isomers and the racemic and non-racemic mixtures of the
isomers.
[0051] Preferable examples of the compound of the present invention
are as follows.
##STR00003##
[0052] That is preferable are compounds of the formula [II] in
which R.sup.1, R.sup.2, R.sup.3 and Ar are as defined in formula
[I]. More preferable are compounds of the formula [II], wherein
R.sup.1 is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is
C.sub.1-6alkyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 and
R.sup.5 are the same or different, and independently hydrogen,
C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; Ar is phenyl which
phenyl is substituted with two or three substituents, which are the
same or different, selected from the group consisting of halogen,
C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.20)R.sup.21
(wherein R.sup.20 and R.sup.21 are the same or different, and
independently are hydrogen or C.sub.1-3alkyl); More preferable are
compounds of the formula [II], wherein R.sup.1 is --OR.sup.4 or
--NR.sup.4R.sup.5; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is hydrogen
or C.sub.1-6alkyl; R.sup.4 is C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; R.sup.5 is
hydrogen; Ar is phenyl which phenyl is substituted with two or
three substituents, which are the same or different, selected from
the group consisting of halogen and C.sub.1-3alkyl.
##STR00004##
[0053] Other preferable are compounds of the formula [III] in which
R.sup.1, R.sup.2, R.sup.3 and Ar are as defined in formula [I].
More preferable are compounds of the formula [III], wherein R.sup.1
is --OR.sup.4 or --NR.sup.4R.sup.5; R.sup.2 is C.sub.1-6alkyl;
R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.4 and R.sup.5 are the
same or different, and independently hydrogen, C.sub.1-9alkyl,
C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; Ar is phenyl which
phenyl is substituted with two or three substituents, which are the
same or different, selected from the group consisting of halogen,
C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.1-3alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.20)R.sup.21
(wherein R.sup.20 and R.sup.21 are the same or different, and
independently are hydrogen or C.sub.1-3alkyl); More preferable are
compounds of the formula [III], wherein R.sup.1 is --OR.sup.4 or
--NR.sup.4R.sup.5; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is hydrogen
or C.sub.1-6alkyl; R.sup.4 is C.sub.1-9alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
di(C.sub.3-7cycloalkyl)-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl, di(C.sub.1-6alkoxy)-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or cyano-C.sub.1-6alkyl; R.sup.5 is
hydrogen; Ar is phenyl which phenyl is substituted with two or
three substituents, which are the same or different, selected from
the group consisting of halogen and C.sub.1-3alkyl.
[0054] The compound of the formula [I] can be produced, for
example, by the process shown in the following reaction scheme 1
(in the following reaction scheme, R.sup.1, R.sup.2, R.sup.3 and Ar
are as defined above, LG is chloro, bromo, iodo,
methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or
trifluoromethanesulfonyloxy group, R.sup.a is C.sub.1-6alkyl or
benzyl, p is 1 or 2).
##STR00005##
Step 1:
[0055] Compound (2) can be obtained by reacting Compound (1) with
the corresponding amine in an inert solvent in the presence or
absence of a base. Herein, the base includes, for example, amines
such as triethylamine, N,N-diisopropylethylamine, pyridine and the
like; inorganic bases such as sodium carbonate, potassium
carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate,
potassium hydroxide, sodium hydroxide, lithium hydroxide, barium
hydroxide, sodium hydride and the like; metal alcoholates such as
sodium methoxide, sodium ethoxide, potassium tert-butoxide and the
like; metal amides such as sodium amide, lithium diisopropylamide
and the like; and Grignard reagents such as methylmagnesium bromide
and the like. The inert solvent includes, for example, alcohols
such as methanol, ethanol, isopropyl alcohol, ethylene glycol and
the like; ethers such as diethyl ether, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as
benzene, toluene, xylene and the like; esters such as ethyl
acetate, ethyl formate; amides such as N,N-dimethylformamide,
N-methylpyrrolidone, N,N-dimethylacetamide and the like;
acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide;
pyridine; water; and mixtures of solvents selected from these inert
solvents.
Step 2:
[0056] Conversion of a cyano group in Compound (2) into a carbamoyl
group can be achieved in the presence of an acid or a base in the
presence or absence of an inert solvent. When R.sup.1 has a cyano
group, the cyano group can be converted into a carbamoyl group at
the same time. Herein, the acid includes inorganic acids such as
sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric
acid, polyphosphoric acid nitric acid and the like; organic acids
such as benzenesulfonic acid, toluenesulfonic acid and the like.
The base includes inorganic bases such as lithium hydroxide, sodium
hydroxide, potassium hydroxide, calcium hydroxide, magnesium
hydroxide, zinc hydroxide, aluminium hydroxide and the like. The
inert solvent includes, for example, alcohols such as methanol,
ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol and
the like; ethers such as diethyl ether, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as
benzene, toluene and the like; amides such as
N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide
and the like; acetonitrile; dichloromethane; chloroform; dimethyl
sulfoxide; pyridine; water; and mixtures of solvents selected from
these inert solvents.
[0057] The compound of the present invention can be converted to a
salt with an acid in an inert solvent. The acid includes inorganic
acids such as sulfuric acid, hydrochloric acid, hydrobromic acid,
phosphoric acid, nitric acid and the like; organic acids such as
acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid,
maleic acid, citric acid, benzenesulfonic acid, methanesulfonic
acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid,
ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic
acid, glycolic acid, malic acid, malonic acid, mandelic acid,
galactaric acid, naphthalene-2-sulfonic acid and the like.
[0058] The inert solvent includes, for example, alcohols such as
methanol; ethanol, isopropyl alcohol, ethylene glycol and the like;
ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane and the like; hydrocarbons such as benzene,
toluene and the like; amides such as N,N-dimethylformamide,
N-methylpyrrolidone, N,N-dimethylacetamide and the like; esters
such as ethyl acetate, ethyl formate and the like; ketones such as
acetone, methylethylketone and the like; acetonitrile;
dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water;
and mixtures of solvents selected from these inert solvents.
##STR00006##
Step 3:
[0059] Conversion of Compound (4) into Compound (5) can be carried
out by treatment of (4) with thiourea in an inert solvent and
followed by reacting with an alkylating reagent in the presence or
absence of a base in an inert solvent. Herein, the alkylating
reagent includes conventional alkylating reagents such as methyl
iodide, methyl bromide, dimethyl sulfate, ethyl iodide, ethyl
bromide, diethyl sulfate, benzyl chloride, benzyl bromide and the
like. The base includes amines such as triethylamine,
N,N-diisopropylethylamine, pyridine and the like; inorganic bases
such as sodium carbonate, potassium carbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, potassium
hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide,
sodium hydride and the like; metal alcoholates such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide and the like;
metal amides such as sodium amide, lithium diisopropylamide and the
like; and Grignard reagents such as methylmagnesium bromide and the
like. The inert solvent includes, for example, alcohols such as
methanol, ethanol, isopropyl alcohol, ethylene glycol and the like;
ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane and the like; hydrocarbons such as benzene,
toluene, xylene and the like; amides such as N,N-dimethylformamide,
N-methylpyrrolidone, N,N-dimethylacetamide and the like;
acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide;
pyridine; water; and mixtures of solvents selected from these inert
solvents.
Step 4:
[0060] Conversion of Compound (5) into Compound (6) can be achieved
in the same manner as step 2.
Step 5:
[0061] Conversion of Compound (6) into Compound (7) can be carried
out by reacting Compound (6) with an oxidizing reagent in an inert
solvent. Herein, the oxidizing reagent includes conventional
oxidizing reagents to oxidize a sulfide group such as peroxyacetic
acid, hydrogen peroxide, 3-chloroperoxybenzoic acid, Oxone, sodium
periodate, sodium perborate and the like. The inert solvent
includes, for example, alcohols such as methanol, ethanol,
isopropyl alcohol, ethylene glycol and the like; ethers such as
diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane
and the like; hydrocarbons such as benzene, toluene, xylene and the
like; amides such as N,N-dimethylformamide, N-methylpyrrolidone,
N,N-dimethylacetamide and the like; acetonitrile; dichloromethane;
chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of
solvents selected from these inert solvents.
Step 6:
[0062] Conversion of Compound (7) into Compound (8) can be carried
out in the same manner as step 1.
[0063] The compound of the present invention is useful as a
therapeutic or prophylactic agent for diseases in which CRF is
considered to be involved. For this purpose, the compound of the
present invention can be formulated into tablets, pills, capsules,
granules, powders, solutions, emulsions, suspensions, injections
and the like by a conventional preparation technique by adding
conventional fillers, binders, disintegrators, pH-adjusting agents,
solvents, etc.
[0064] The compound of the present invention can be administered to
an adult patient in a dose of 0.1 to 500 mg per day in one portion
or several portions orally or parenterally. The dose can be
properly increased or decreased depending on the kind of a disease
and the age, body weight and symptom of a patient.
EMBODIMENTS OF THE INVENTION
[0065] The present invention is concretely explained with reference
to the following examples and test example, but is not limited
thereto.
EXAMPLE 1
Synthesis of
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[-
1,2-a]pyrimidine-6-carboxylic acid amide hydrochloride (Compound
1-001)
##STR00007##
[0067] (1) A mixture of
8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidin-
e-6-carbonitrile (30.0 g), 1-propyl-butylamine (18.5 g),
N,N-diisopropylethylamine (15.5 g) in ethanol (90 mL) was heated at
reflux for 2 h. The reaction mixture was cooled to room
temperature, poured into a saturated aqueous sodium
hydrogencarbonate, and then extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure to give a solid. The solid was washed with
diisopropylether to give
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[-
1,2-a]pyrimidine-6-carbonitrile (27.0 g).
##STR00008##
[0068] (2)
8-(4-Bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino-
)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (10.0 g) was added into
conc. H.sub.2SO.sub.4 (50 mL) and heated for 55.degree. C. for 5
hours. The reaction mixture was cooled to room temperature, poured
into ice-water and then a saturated aqueous sodium
hydrogencarbonate was added to make the aqueous mixture alkaline
(pH=8) and extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure and
the residue was purified by a silica gel column chromatography
(silica gel: Wako Gel (C200), eluent: hexane/ethyl
acetate/chloroform=10:3:1) to give a solid. The solid was
recrystallized from ethyl acetate to provide
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[-
1,2-a]pyrimidine-6-carboxylic acid amide (5.8 g).
[0069] (3) To a suspension of
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[-
1,2-a]pyrimidine-6-carboxylic acid amide (5.8 g) in ethanol (30 mL)
was added 4 M HCl/ethyl acetate (3.7 mL) in an ice-cooling bath.
The resulting solution was concentrated under reduced pressure. The
residue was crystallized from ethyl acetate to give the title
compound.
[0070] Table 1 and table 2 list the compound obtained in Example 1
and compounds obtained by the similar procedure as described in
Example 1.
EXAMPLE 2
Synthesis of
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(N,N-dipropylamino)-pyrrolo[1,-
2-a]pyrimidine-6-carboxylic acid amide (Compound 1-022)
##STR00009##
[0072] (1) A mixture of
8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidin-
e-6-carbonitrile (7.50 g), thiourea (7.11 g) in ethanol (50 mL) was
heated at reflux for 2 h. The reaction mixture was cooled to room
temperature, poured into 0.5 M NaOH aqueous solution, stirred for 1
hour and extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated under reduced pressure and the residue
was purified by a silica gel column chromatography (silica gel:
Wako Gel (C200), eluent: chloroform/methanol=10:1) to give
8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimid-
ine-6-carbonitrile (7.52 g).
##STR00010##
[0073] (2) A mixture of
8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimid-
ine-6-carbonitrile (7.50 g), MeI (12.5 mL) in 1 M NaOH aqueous
solution (100 mL) was stirred at room temperature for 1 h. The
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated under reduced pressure
to give crude
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]p-
yrimidine-6-carbonitrile (5.75 g). This product was used in the
next step without further purification.
##STR00011##
[0074] (3)
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrro-
lo[1,2-a]pyrimidine-6-carbonitrile (5.70 g) was added into conc.
H.sub.2SO.sub.4 (100 mL) and heated for 60.degree. C. for 5 hours.
The reaction mixture was cooled to room temperature, poured into
ice-water and then 10% aqueous NaOH solution was added to make the
aqueous mixture alkaline (pH=8) and extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by a silica gel
column chromatography (silica gel: Wako Gel (C200), eluent: ethyl
acetate) to give
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]p-
yrimidine-6-carboxylic acid amide (3.12 g).
##STR00012##
[0075] (4) To a solution of Oxone (9.12 g) in water (50 mL) was
added a solution of
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]p-
yrimidine-6-carboxylic acid amide (3.00 g) in ethanol (50 mL) in an
ice-cooling bath. The reaction mixture was stirred under
ice-cooling for 30 minutes, poured into water and extracted with
ethyl acetate. The organic layer was washed with a saturated
aqueous sodium hydrogencarbonate and brine, dried over anhydrous
sodium sulfate and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by a silica gel
column chromatography (silica gel: Wako Gel (C200), eluent: ethyl
acetate) to give
8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]-
pyrimidine-6-carboxylic acid amide (1:68 g).
##STR00013##
[0076] (5) A mixture of
8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]-
pyrimidine-6-carboxylic acid amide (100 mg), N,N-dipropylamine (48
mg) in ethanol (1 mL) was heated at reflux for 1 h. The reaction
mixture was cooled to room temperature, poured into a saturated
aqueous sodium hydrogencarbonate, and then extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by
a silica gel column chromatography (silica gel: Wako Gel (C200),
eluent: hexane/ethyl acetate=1:1) to give a solid. The solid was
washed with a mixture of diisopropylether and ethyl acetate to give
the title compound (50 mg).
[0077] Table 1 lists the compound obtained in Example 2 and
compounds obtained by the similar procedure as described in Example
2.
TABLE-US-00001 TABLE 1.sup.*1 ##STR00014## Com. No. Ex. No.
##STR00015## R.sup.2 R.sup.3 ##STR00016## melting point (.degree.
C.) (solvent for crystallization) 1-001 1 ##STR00017## CH.sub.3 H
##STR00018## 163-165.sup.*2 (EtOAc/EtOH) 1-002 1 ##STR00019##
CH.sub.3 H ##STR00020## 195-197.sup.*2 (EtOAc/EtOH) 1-003 1
##STR00021## CH.sub.3 H ##STR00022## 213-215.sup.*2 (EtOAc/EtOH)
1-004 1 ##STR00023## CH.sub.3 H ##STR00024## 204-206.sup.*2
(EtOAc/EtOH) 1-005 1 ##STR00025## CH.sub.3 H ##STR00026##
203-205.sup.*2 (EtOAc/EtOH) 1-006 1 ##STR00027## CH.sub.3 H
##STR00028## 180-182.sup.*2 (EtOAc/EtOH) 1-007 1 ##STR00029##
CH.sub.3 H ##STR00030## 166-168.sup.*2 (EtOAc/EtOH) 1-008 1
##STR00031## CH.sub.3 H ##STR00032## 175-177.sup.*2 (EtOAc/EtOH)
1-009 1 ##STR00033## CH.sub.3 H ##STR00034## 172-174.sup.*2
(EtOAc/EtOH) 1-010 1 ##STR00035## CH.sub.3 H ##STR00036##
160-162.sup.*2 (EtOAc/EtOH) 1-011 1 ##STR00037## CH.sub.3 H
##STR00038## 172-174.sup.*2 (EtOAc/EtOH) 1-012 1 ##STR00039##
CH.sub.3 H ##STR00040## 166-168.sup.*2 (EtOAc/EtOH) 1-013 1
##STR00041## CH.sub.3 H ##STR00042## 203-205.sup.*2 (EtOAc/EtOH)
1-014 1 ##STR00043## CH.sub.3 H ##STR00044## 188-190.sup.*2
(EtOAc/EtOH) 1-015 1 ##STR00045## CH.sub.3 H ##STR00046##
183-185.sup.*2 (EtOAc) 1-016 1 ##STR00047## CH.sub.3 H ##STR00048##
180-182.sup.*2*3 1-017 1 ##STR00049## CH.sub.3 H ##STR00050##
163-165.sup.*2*3 1-018 2 ##STR00051## CH.sub.3 H ##STR00052##
240-242 (EtOAc) 1-019 2 ##STR00053## CH.sub.3 H ##STR00054##
232-234 (decomp.) (EtOAc) 1-020 2 ##STR00055## CH.sub.3 H
##STR00056## 199-201 (EtOAc) 1-021 2 ##STR00057## CH.sub.3 H
##STR00058## 208-210 (EtOAc) 1-022 2 ##STR00059## CH.sub.3 H
##STR00060## 178-180 (EtOAc) 1-023 2 ##STR00061## CH.sub.3 H
##STR00062## 194-196.sup.*3 1-024 2 ##STR00063## CH.sub.3 H
##STR00064## amorphous 1-025 2 ##STR00065## CH.sub.3 H ##STR00066##
223-225 (EtOAc) 1-026 2 ##STR00067## CH.sub.3 H ##STR00068##
227-229 (EtOAc) 1-027 2 ##STR00069## CH.sub.3 H ##STR00070##
222-224 (EtOAc) 1-028 1 ##STR00071## CH.sub.3 H ##STR00072##
amorphous .sup.*1Com. No. = compound number, Ex. No. = example
number, solvent for crystallization; EtOAc = ethyl acetate, EtOH =
ethanol Analytical data of non-crystal compounds are described
below. 1-024: MS (Pos, ES): 442 (M + Na).sup.+, 444 (M + Na +
2).sup.+; NMR (300 MHz, CDCl.sub.3) .delta. 2.04 (3 H, s), 2.09 (3
H, s), 2.58 (3 H, s), 3.17 (3 H, s), 5.54-5.66 (2 H, m), 7.26 (1 H,
s), 7.31 (2 H, s), 7.59 (1 H, s) 1-028: MS (Pos, ES): 486 (M +
1).sup.+, 488 (M + 3).sup.+, 508 (M + Na).sup.+, 510 (M + Na +
2).sup.+; NMR (300 MHz, CDCl.sub.3) .delta. 0.98 (3 H, t, J = 7.3
Hz), 1.40-1.64 (2 H, m), 1.68-1.79 (2 H, m), 2.09 (3 H, s), 2.10 (3
H, s), 2.37 (3 H, s), 2.51 (1 H, dd, J = 5.9, 14.4 Hz), 2.65 (1 H,
dd, J = 7.4, 14.4 Hz), 4.07-4.18 (1 H, m), 5.28-5.39 (1 H, br s),
5.48-5.58 (2 H, br s), 5.72-5.87 (1 H, br s), 5.89 (1 H, s), 7.22
(1 H, s), 7.26 (3 H, s), 10.75-10.92 (1 H, br s) .sup.*2HCl salt
(Compound 1-015 is 2HCl salt) .sup.*3Crystallized on standing from
the compound purified (silica gel column chromatography) and
dried.
TABLE-US-00002 TABLE 2.sup.*1 ##STR00073## Com. No. Ex. No.
##STR00074## R.sup.2 R.sup.3 ##STR00075## melting point (.degree.
C.) (solvent for crystallization) 2-001 1 ##STR00076## CH.sub.3 H
##STR00077## 225-227.sup.*2 (EtOAc/IPE) 2-002 1 ##STR00078##
CH.sub.3 H ##STR00079## 244-246.sup.*2 (EtOAc) 2-003 1 ##STR00080##
CH.sub.3 H ##STR00081## 229-231.sup.*2 (EtOAc) 2-004 1 ##STR00082##
CH.sub.3 H ##STR00083## 214-216.sup.*2 (EtOAc) 2-005 1 ##STR00084##
CH.sub.3 H ##STR00085## 218-220.sup.*2 (EtOAc) 2-006 1 ##STR00086##
CH.sub.3 H ##STR00087## 206-208.sup.*2 (decomp.) (EtOAc)
.sup.*1Com. No. = compound number, Ex. No. = example number,
solvent for crystallization; EtOAc = ethyl acetate, IPE =
diisopropylether .sup.*2HCl salt
Test Example [CRF Receptor Binding Test]
[0078] Monkey amygdala membranes were used as a receptor
preparation.
[0079] .sup.125I-CRF was used as .sup.125I-labeled ligand.
[0080] Binding reaction using the .sup.125I-labeled ligand was
carried out by the following method described in The Journal of
Neuroscience, 7, 88 (1987).
Preparation of receptor membranes:
[0081] Monkey amygdala was homogenized in 50 mM Tris-HCl buffer (pH
7.0) containing 10 mM MgCl.sub.2, 2 mM EDTA and centrifuged at
48,000.times.g for 20 min, and the precipitate was washed once with
Tris-HCl buffer. The washed precipitate was suspended in 50 mM
Tris-HCl buffer (pH 7.0) containing 10 mM MgCl.sub.2, 2 mM EDTA,
0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to
obtain a membrane preparation.
CRF receptor binding test:
[0082] The membrane preparation (0.3 mg protein/ml), .sup.125I-CRF
(0.2 nM) and a test drug were reacted at 25.degree. C. for 2 hours.
After completion of the reaction, the reaction mixture was filtered
by suction through a glass filter (GF/C) treated with 0.3%
polyethylene imine, and the glass filter was washed three times
with phosphate-buffered saline containing 0.01% Triton X-100. After
the washing, the radioactivity of the filter paper was measured in
a gamma counter.
[0083] The amount of .sup.125I-CRF bound when the reaction was
carried out in the presence of 1 .mu.M CRF was taken as the degree
of nonspecific binding of .sup.125I-CRF, and the difference between
the total degree of .sup.125I-CRF binding and the degree of
nonspecific .sup.125I-CRF binding was taken as the degree of
specific .sup.125I-CRF binding. An inhibition curve was obtained by
reacting a definite concentration (0.2 nM) of .sup.125I-CRF with
various concentrations of each test drug under the conditions
described above. A concentration of the test drug at which binding
of .sup.125I-CRF is inhibited by 50% (IC.sub.50) was determined
from the inhibition curve.
[0084] As a result, it was found that compounds 1-001, 1-002,
1-003, 1-004, 1-005, 1-006, 1-007, 1-008, 1-009, 1-010, 1-011,
1-012, 1-013, 1-016, 1-017, 1-018, 1-019, 1-022, 1-027, 2-001,
2-002, 2-003, 2-004, 2-005 and 2-006 can be exemplified as typical
compounds having an IC.sub.50 value of 100 nM or less.
EFFECT OF THE INVENTION
[0085] According to the present invention, compounds having a high
affinity for CRF receptors have been provided. These compounds are
effective against diseases in which CRF is considered to be
involved, such as depression, anxiety, Alzheimer's disease,
Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc.
* * * * *